Pyridazinones

ABSTRACT

Compounds of the general formula: ##SPC1## 
     In which X represents a straight or branched chain alkyl or alkoxy group, a hydroxymethyl group, a cycloalkyl group, a cycloalkoxy group, an aryloxy group, a hydroxyl group, a fluorine atom, a chlorine atom, an amino or substituted amino group, a piperidino group, a morpholino group, a pyrrolidino group, a 1,2,3,6-tetrahydropyridino group, a 4-[3-azabicyclo(3,2,2)-nonyl] group, or a 4-(piperazin-1-yl) or 4-(4-substituted-piperazin-1-yl) group of the formula ##SPC2## 
     In which R=H, lower alkyl or 1-5 carbon atoms, aryl, substituted aryl, aralkyl, cinnamyl, acyl, ethoxy-carbonyl, aroyl or substituted aroyl and n is an integer from 1 to 5 except that when n is 1 X is not an alkyl group of 1 to 3 carbon atoms or an alkoxy group of 1 or 2 carbon atoms or a chlorine atom in the 4&#39;-position, or an amino or acylated amino group in positions 2&#39;, 3&#39; or 4&#39;; and when n = 2 the groups X cannot both be methyl or both be methoxy in the 2&#39; and 5&#39; positions, nor can X be a chlorine atom in both the 2&#39; and 4&#39; positions or the 3&#39; and 4&#39; positions, and when n = 3, X cannot all three be methoxy. These compounds have anti-hypertensive activity.

This is a continuation of application Ser. No. 225,270, filed Feb. 10,1972, now abandoned.

This invention relates to novel pyridazinones and to a process for theproduction thereof and to pharmaceutical compositions containing suchpyridazinones.

We have found, according to the invention, that certain pyridazinoneshave an anti-hypertensive activity which is in some cases quite markedand is not associated with as many side reactions as may be encounteredwith known anti-hypertensive drugs.

The invention provides compounds of the general formula: ##SPC3##

In which X represents a straight or branched chain alkyl or alkoxygroup, a hydroxymethyl group, a cycloalkyl group, a cycloalkoxy group,an aryloxy group, a hydroxyl group, a fluorine atom, a chlorine atom, anamino or substituted amino group, a piperidino group, a morpholinogroup, a pyrrolidino group, a 1,2,3,6-tetrahydropyridino group, a4-[3-azabicyclo(3,2,2)-nonyl] group, or a 4-(piperazin-1-yl) or4-(4-substituted-piperazin-1-yl) group of the formula ##SPC4##

In which R=H, lower alkyl of 1-5 carbon atoms, aryl, substituted aryl,aralkyl, cinnamyl, acyl, ethoxy-carbonyl, aroyl or substituted aroyl andn is an integer from 1 to 5 except that when n is 1 X is not an alkylgroup of 1 to 3 carbon atoms or an alkoxy group of 1 or 2 carbon atomsor a chlorine atom in the 4'-position, or an amino or acylated aminogroup in positions 2', 3' or 4' and when n = 2, the group X cannot bothbe methyl or both be methoxy in the 2' and 5' positions, nor can X be achlorine atom in both the 2' and 4' positions or the 3' and 4' positionsand when n = 3, X cannot all three be methoxy.

A preferred sub-class of compounds are those in which X is piperidino ormorpholino or an alkoxy group containing from 1 to 12 carbon atoms,subject to the proviso specified above. Specific preferred compoundsaccording to the invention are those the preparation of which isdescribed in the Examples. Particularly preferred compounds are thefollowing:

6-(o-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, (Example 1),

6-(p-piperidinophenyl)-4,5-dihydro-3(2H)-pyridazinone (Example 2),

6-(p-morpholinophenyl)-4,5-dihydro-3(2H)-pyridazinone (Example 3),

6-(o-ethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (Example 7), and

6-(p-hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone, (Example 8).

Of these compounds the second mentioned and the last mentioned areparticularly useful.

The compounds according to the invention may be prepared by a number ofprocesses. In one process the parent 3-substituted benzoylpropionic acidII may be heated with hydrazine hydrate as indicated below ##SPC5##

This reaction may be carried out by heating the components togetherpreferably in solution under suitable conditions for example underreflux and recovering the product by cooling when the productcrystallizes and can be separated off and if desired recrystallised.

In an alternative process, for the production of compounds in which Xrepresents an alkoxy group the parent hydroxyphenyl pyridazinone can bealkylated directly using an alkylating agent such as alkyl halide in thepresence of an acid binding agent, as follows: ##SPC6##

This alkylation may conveniently be carried out by heating thehydroxyphenyl compound with the alkylating agent under conditions ofreflux in the presence of an acid binding agent. Suitable alkylatingagents include for example 1-bromopropane, 1-bromohexane,1-iodo-3-methybutane and similar alkyl halides. Suitable acid bindingagents include alkali metal hydroxides or carbonates such as potassiumcarbonate.

As will be appreciated the hydroxyphenyl pyridazinone is a compoundaccording to the invention and accordingly the second process representsa subsequent conversion of the first (I; X=OH). Similarly3-(p-substituted benzoyl) propionic esters of the acids II in which Xrepresents a basic or heterocyclic moiety may be prepared from esters ofthe acids (II; X=p-fluoro) by reaction of such compounds with theappropriate base or heterocyclic base.

The parent acid II used as starting material may be prepared by a numberof methods including for example the Friedel Crafts reaction between theappropriate substituted phenyl ether and succinic anhydride, reaction ofa phenol with succinic anhydride and aluminium chloride, demethylationof the p-methoxy acid, reaction of the dialkoxybenzene with succinicanhydride and aluminium chloride and reaction of fluorobenzene with thesame reagents. These reactions are appropriate to the production of theortho- and/or para-acids. The meta-acids may be prepared by standardmethods starting with the nitration of 3-p-benzoylpropionic acid toyield the m nitro acid, which may be reduced to the m-amino acid,diazotised to yield the m-chloro acid or the m-hydroxy acid which lattermay be alkylated to the m-alkoxy acid.

The compounds according to the invention may be formulated foradministration in association with a pharmaceutically acceptable carrierand the invention extends to such pharmaceutical compositions. Thepharmaceutical compositions may be in any desired form and may beliquid, semi-solid or solid. As a liquid it may be in the form of aninjectable solution wherein the carrier is sterile, non-pyrogenic water.It may also be in the form of a liquid for oral administration e.g. asan elixir or syrup which may contain adjuvants usual in suchformulations. It may also be formulated as a capsule. The compositionmay also be in solid form, a particularly preferred form ofadministration being as a tablet. A suitable dose of the active compoundis from 20 to 200 mg. per day and the pharamaceutical composition may beso formulated as to provide the whole or a proportion of such dose in asingle dosage unit.

The following Examples illustrate the invention:

EXAMPLE 1 6-(p-Cyclopentylphenyl)-4,5-dihydro-3(2H)-pyridazinone

A solution of 3-(p-cyclopentylbenzoyl)propionic acid (4.9 g.) in warmethanol (50 ml.) was treated with hydrazine hydrate (1.1 g.) and themixture heated on the steam bath for 1 hour. The colourless crystallinematerial which separated, was collected and recrystallised from ethanolto yield the product (4.2 g.) in large, colourless needles, m.p.191°-192°C.

Similarly obtained by the reaction of the appropriately substitutedbenzoyl propionic acid with hydrazine hydrate were:

6-(p-Phenoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 147°-148°C

6-(p-Cyclohexylphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 201°-203°C

6-(p-Hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. > 300°C

6-(o-Hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 216°-217°C

6-(p-Butoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 136°-137°C

6-(p-Fluorophenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 196°-198°C

6-(o-Methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 120°-122°C

6-(m-Hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 260°-263°C

6-(m-Methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 129°-131°C

6-(3,4-dimethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 169°-170°C

6-(3,4-dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 305°C (withdecomposition)

6-(2,5-Dihydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 289°-291°C

6-(2-hydroxy-5-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p.198°-200°C

6-(2-hydroxy-4-methylphenyl)-4,5-dihydro-3-(2H)-pyridazinone m.p.209°-210°C

6-(2-methoxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p.142°-143°C

example 2 6-(p-Piperidinophenyl)-4,5-dihydro-3(2H)-pyridazinone a.Methyl 3-(p-fluorobenzoyl)propionate

A solution of 3-(p-fluorobenzoyl)propionic acid (58.8 g.) in anhydrousmethanol (250 ml.) was treated with concentrated sulphuric acid (3.2ml.) and the mixture heated at reflux temperature for 10 hours. It wasthen concentrated to a volume of 100 ml., cooled and diluted withice-water. The resultant solid was collected and crystallised fromligroin to yield the ester (59.7 g.), m.p. 48°-50°C.

b. Methyl 3-(p-piperidinobenzoyl)propionate

A solution of the foregoing ester (42.0 g.) in dimethylsuphoxide (150ml.) was treated with piperidine (17.0 g.), followed by anhydrouspotassium carbonate (27.6 g) and the mixture was stirred and heated at100°C for 30 hours. It was then cooled and poured into ice-water (1litre) and the solid which precipitated was collected, washed well withcold water and dried (Yield 51.7 g, m.p. 67°-69°C). It was purified bycrystallisation from methanol to yield the basic ester in fine pale,lemon-yellow needles, m.p. 72°-73°C.

c. 3-(p-Piperidinobenzoyl)propionic acid

A solution of the foregoing ester (20 g.) in ethanol (100 ml.) wastreated with a solution of sodium hydroxide (4.0 g.) in water (100 ml.)and the mixture was heated at reflux temperature for 6 hours. It wasthen concentrated to half bulk to remove most of the ethanol, dilutedwith water (150 ml.), cooled and extracted with ether to remove anyunchanged ester. The aqueous layer was adjusted to pH 4-5 by theaddition of dilute (3N) hydrochloric acid and the precipitated solid wascollected and washed with ice-cold water. It was crystallised fromaqueous ethanol to yield the acid (17 g.), m.p. 150°-151°C.

d. 6-(p-Piperidinophenyl)-4,5-dihydro-3(2H)-pyridiazinone

A solution of 3-(p-piperidinobenzoyl)propionic acid (7.1 g) in ethanol(65 ml.) was treated with hydrazine hydrate (1.5 g.) and the mixtureheated at reflux temperature for 3 hours. It was then cooled and thesolid collected and washed with a little cold ethanol. It wascrystallised from a mixture of ethanol and 1,2-dichlorethane to yieldthe title product (5 g.), m.p. 242°-244°C.

The product was obtained in smaller yield whenmethyl-3-(p-piperidinobenzoyl)propionate (5.5 g.) and hydrazine hydrate(1.1 g.) were heated in ethanol (50 ml.) at reflux temperature for 3hours.

EXAMPLE 3 6-(p-Morpholinophenyl)-4,5-dihydro-3(2H)-pyridazinone a.Methyl 3-(p-morpholinobenzoyl)propionate

A solution of methyl 3-(p-fluorobenzoyl) propionate (42.0 g.) indimethylsulphoxide (150 ml.) was treated with morpholine (17.4 g.)followed by anhydrous potassium carbonate (27.6 g.) and the mixture wasstirred and heated at 100°C for 30 hours. It was then cooled, pouredinto ice-water (1 litre) and the precipitated solid collected, washedwith cold water and dried. It was crystallised twice from methanol toyield the ester (23.1 g), m.p. 120°-121°C.

b. 3-(p-Morpholinobenzyl)propionic acid

A solution of the foregoing ester (19.4 g.) in ethanol (100 ml.) wastreated with a solution of sodium hydroxide (4.0 g.) in water (100 ml.)and the mixture heated at reflux temperature for 6 hours. It wasconcentrated to about one third bulk, diluted with water (150 ml.) andextracted with ether to remove any unchanged ester. The aqueous layerwas adjusted to pH 2 by addition of 3N hydrochloric acid whenprecipitation occurred. The solid was collected, washed with cold waterand dried. Cyrstallisation from ethanol furnished the pure acid (15.5g.), m.p. 167°-168°C.

c. 6-(p-Morpholinophenyl)-4,5-dihydro-3(2H)-pyridazinone

A solution of 3-(p-morpholinobenzoyl)propionic acid (11.7 g.) in warmethanol (150 ml.) was treated with hydrazine hydrate (2.5 g.) and themixture heated at reflux temperature for 4 hours. It was then cooled andthe solid collected (11.0 g; m.p. 226°-229°C). This was crystallisedfrom a mixture of ethanol (100 ml.) and 1,2-dichloroethane (150 ml.) toyield the product as colourless needles, m.p, 225°-228°C.

Similarly prepared by the reaction of an appropriate amine with methyl3-(p-fluorobenzoyl)propionate followed by hydrolysis and treatment withhydrazine hydrate were:

6-[p-(3-Azabicyclo[3,2,2]-nonylphenyl] -4,5-dihydro-3(2H)-pyridazinonem.p. 273°-275°C

6-[p-(4-Methylpiperazinyl)phenyl]-4,5-dihydro-3(2H)-pyridazinonehemihydrate m.p. 223°-224°C.

6-[p-(1,2,3,6-Tetrahydropyridino)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 222°-228°C (with decomposition)

6-[p-Pyrrolidinophenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 296°C (withdecomposition

6-[p-(4Benzylpiperazin1-yl)phenyl]-4,5-dihydro-3(2H)pyradazinone m.p.180°-182°C.

6-[p-(4-Benzoylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 264°-265°C

6-[p-(4-phenethylpiperazin-1-yl]-4,5-dihydro-3(2H)-pyridazinone m.p.255°-257°C

6-[p-(4-Phenylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.296°-297°C

6-[p-(4-Ethoxycarbonylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 221°-222°C

6-[p-(4-o-Methoxyphenylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 217°-218°C

6-[p-(4-p-Methoxyphenylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 264°-266°C

6-[p-(4-p-Tolylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 268°-270°C.

6-[p-(4-o-Ethoxyphenylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinonem.p. 218°-219°C.

6-[p-(4-Ethylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.224°-225°C.

6-[p-(4-Pentylpiperazin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.184°-185°C.

EXAMPLE 4 6-(p-Propoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a.Ethyl-3-(p-propoxybenzoyl)propionate

To a solution of ethyl 3-(p-hydroxybenzoyl propionate (31.0 g.) inacetone (300 ml.) was added anhydrous potassium carbonate (15.2 g.) and1-bromopropane (17.2 g.) and the mixture was heated at refluxtemperature for 12 hours. It was then cooled, poured into ice-waater (1litre) and the oil isolated with methylene dichloride. It was purifiedby distillation at reduced pressure and had bp 168°-170° at 0.2 mm;n_(D) ²⁴.5 = 1.5200.

b. 3-(p-propoxybenzoyl)propionic acid

This was prepared in 90% yield by hydrolysis of the foregoing ester withsodium hydroxide in aqueous ethanol and had mp 116°-117°C.

c. 6-(p-Propoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

This was prepared in 83% yield by reaction of the foregoing acid withhydrazine hydrate as described in the earlier Examples and had mp154°-155°C after crystallisation from ethanol.

Similarly prepared by the reaction of the appropriate alkyl halide withethyl 3-(p-hydroxybenzoyl) propionate followed by hydrolysis andtreatment with hydrazine hydrate were:

6-(p-Isopropoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 174°-175°C

6-[p-(3-Methylbutoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.126°-127°C

6-(p-Hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 110°-111°C

6-[p-(1-Ethylpropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.127°-128.5°C

6-(p-n. Octyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 120°-121°C

6-(p-n. Nonyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 125°-126.5°C

6-(p-Decyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 130°-132°C

6-[p-(1-Ethylbutoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone m.p.109°-111°C

6-(p-Dodecyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 165°-135°C

6-(p-Heptyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 106°-107°C

example 5 6-(p-Propoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

A solution of 6-(p-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (7.7g.), in ethanol (80 ml. containing sodium hydroxide (1.7 g.) was treatedwith 1-bromopropane (5.4 g.) and the mixture was heated at refluxtemperature for 21/2 hours. The solid which separated on cooling wascollected and recrystallised from ethanol to yield the pyridazinone (4.4g.), m.p. 154°-155°C. The product was identical with that prepared by analternative route (Example 4).

EXAMPLE 6 6-(p-Cyclohexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a.3-(p-Cyclohexyloxybenzoyl)propionic acid

A solution of succinic anhydride (20 g.) and phenoxycyclohexane (35.1g.) in 1,2-dichloroethane (250 ml.) was stirred at 0°C and treated withpowdered anhydrous aluminium chloride (58.2 g.) and stirring wascontinued for 5 hours at 0°-5°C. It was then poured carefully withstirring into ice-water (1 liter) containing concentrated hydrochloricacid (100 ml.). The organic layer was separated, washed with water andextracted with a solution of sodium hydroxide (8 g.) in water (250 ml.).The alkaline extract was adjusted to pH 4-6 by the addition of dilutehydrochloric acid to yield the product (6.8 g.), m.p. 190°-192°C aftercrystallisation from aqueous methanol.

b. 6-(p-Cyclohexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

This was prepared in 80% yield by reaction of the foregoing acid withhydrazine hydrate in ethanol at reflux temperature for 4 hours. It hadm.p. > 300°C after crystallisation from a mixture of ethanol (2 volumes)and isopropanol (1 volume).

Similarly prepared by reaction of the appropriate phenyl ether withsuccinic anhydride followed by treatment with hydrazine hydrate were:

6-(p-Pentyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 124°-126°C

6-(p-Hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 110°-111°C.

EXAMPLE 7 6-(o-Ethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a. Ethyl3-(o-hydroxybenzoyl)propionate

A solution of 3-(o-hydroxybenzoyl)propionic acid (18.8 g.) in ethanol(120 ml.) was treated with concentrated sulphuric acid (1 ml.) and themixture heated at reflux temperature for 12 hours. It was cooled, pouredinto ice-water (350 ml.) and the oily solid isolated with chloroform. It(18.6 g.) was purified by distillation at reduced pressure and had bp112°-113°C at 0.1 mm; n_(D) ²⁴.5 = 1.5301.

b. Ethyl-3-(o-ethoxybenzoyl)propionate

This was prepared in 58% yield by alkylation of the foregoing ester withethyl bromide in ethanolic solution in the presence of 1 equivalent ofpotassium hydroxide. It has bp 135-136°C at 0.15 mm; n_(D) ³².5 =1.5119.

c. 3-(o-Ethoxylbenzoyl)propionic acid

This was prepared in 80% yield by hydrolysis of the foregoing ester withsodium hydroxide in 50% aqueous ethanol and had mp 125°-127°C aftercrystallisation from aqueous ethanol.

d. 6-(o-Ethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

This was obtained in 88% yield by reaction of3-(o-ethoxybebzoyl)propionic acid with hydrazine hydrate at refluxtemperature for 6 hours, and had m.p. 137°-139°C after crystallisationfrom ethanol.

Similarly prepared using hexyl bromide in place of ethyl bromide was:6-(o-Hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone m.p. 75°-77°C.

EXAMPLE 8 6-(3-Amino-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a.3-(3-Amino-4-methoxybenzoyl)propionic acid

A solution of 3-(4-methoxy-3-nitrobenzoyl) propionic acid (10.5 g.) in5N ammonia solution (150 ml.) was added in one portion to a stirred hot(90°C) solution of hydrated ferrous sulphate (90 g.) in water (210 ml.)and stirring was continued for 10 minutes more. The hot mixture wasfiltered through Hyflo and the filtrate was concentrated to 50 ml.volume and neutralised with acetic acid. The mixture was cooled, theprecipitated solid collected and purified by crystallisation from dilutemethanol to yield the amine, (5.5 g.), m.p. 136°-137°C.

b. 6-(3-Amino-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

This was prepared in 95% yield by reaction of3-(3-amino-4-methoxybenzoyl)-propionic acid with hydrazine hydrate inethanolic solution at reflux temperature for 5 hours. It had m.p.218°-220°C after crystallisation from ethanol.

EXAMPLE 9 6(3-Chloro-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a.3-(3-Chloro-4-methoxybenzoyl)propionic acid

A solution of 3-(3-amino-4-methoxybenzoyl) propionic acid (5 g.) inconcentrated hydrochloric acid (25 ml.) was diazotised at 0°C by theaddition of a solution of sodium nitrite (1.54 g.) in water (5 ml.).This diazo solution was added with stirring to a solution containinghydrated copper sulphate (6.3 g.) and sodium chloride (5.4 g.) in water(20 ml.) to which had been added a solution containing sodiummetabisulphite (1.4 g.) and sodium hyroxide (0.9 g.) in water (10 ml.).The mixture was then heated on the steam bath for 30 minutes when asolid separated. The mixture was cooled, the solid collected and washedwith cold water. It was crystallised from methanol to yield the product(4.2 g.), m.p. 187°-189°C.

b. 6-(3-Chloro-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

This compound was prepared in 84% yield by reaction of3-(3-chloro-4-methoxybenzoyl)propionic acid with hydrazine hydrate inethanolic solution at reflux temperature for 5 hours. It had mp194°-195°C after crystallisation from ethanol.

EXAMPLE 10 6-(3-Acetamido-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a. 3-(3-Acetamido-4-methoxybenzoyl)propionicacid

A mixture of 3-(3-amino-4-methoxybenzoyl) propionic acid (15.61 g.) withacetic anhydride (7.14 g.) was treated with concentrated sulphuric acid(2 drops) and heated on the steam bath for 3 hours. It was then cooledand decomposed by the addition of ice. The resultant solid was collectedand crystallised from methanol to yield the product, (10.5 g.), m.p.184°-185°C.

b. 6-(3-Acetamido-4-methoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone

This was obtained in 90% yield by reaction of6-(3-acetamido-4-methoxybenzoyl)-propionic acid with hydrazine hydratein ethanolic solution at reflux temperature for 5 hours, and had m.p.240°-241°C after crystallisation from ethanol.

EXAMPLE 11 6-(4-Hydroxy-3-methoxyphenyl)-4,5-dihydro- 3(2H)-pyridazinonea. 3-(4-Hydroxy-3-methoxybenzoyl)propionic acid

Guaiacol hydrogensuccinate (11.2 g.) was added to a suspension ofanhydrous aluminium chloride (15.5 g.) in 1,2 -dichloroethane (30 ml.)and the mixture was heated at reflux temperature for 24 hours. It wasthen cooled and poured into a mixture of ice and hydrochloric acid, theorganic layer was removed and the residual solid material crystallisedfrom dilute methanol to give the product (5 g.), m.p. 174°-175°C.

b. 6-(4-Hydroxy-3-methoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone

This was obtained in 95% yield when the foregoing acid was heated withhydrazine hydrate in ethanolic solution for 5 hours. It had m.p.209°-210°C after crystallisation from ethanol.

EXAMPLE 12 6-(3-Hydroxymethyl-4-methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone a. Methyl3-(3-chloromethyl-4-methoxybenzoyl)propionate

A solution of methyl 3-(4-methoxybenzoyl) propionate (40 g.) inchloroform (100 ml.) was treated with paraformaldehyde (15 g.) andanhydrous zinc chloride (10 g.). It was then cooled to -4°-0°C, stirredand a slow stream of hydrogen chloride was passed into the mixture untilit was saturated. Stirring was continued for a further 30 minutes atroom temperature when the mixture was poured into cold water and theorganic layer was isolated, washed thoroughly with cold water and driedover anhydrous sodium sulphate. The solvent was distilled off and theresultant solid purified by crystallisation from methanol. It (25 g.)had m.p. 78°-80°C.

b. 3-(3-Hydroxymethyl-4-methoxybenzoyl)propionic acid

The foregoing chloromethyl compound (6.75 g.) was heated with a solutionof potassium hydroxide (5.6 g.). in water (30 ml.) at 100° for 4 hours.It was then cooled and acidified to Congo red by the addition ofhydrochloric acid. The resultant solid was crystallised from methanol toyield the product (2.1 g.), m.p. 217°-218°C.

c. 6-(3-Hydroxymethyl-4-methoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone

A solution of the foregoing acid (2.38 g.) in ethanol (120 ml.) wastreated with hydrazine hydrate (1.1 g.) and the mixture heated at refluxtemperature for 5 hours. The product crystallised on cooling and hadm.p. 207°-208°C after recrystallisation from ethanol. Yield (1.2 g.).

EXAMPLE 13 6-(p-Piperazin-1-yl)phenyl-4,5 -dihydro-3(2H)-pyridazinonehydrochloride a. Methyl 3-[p-(4-ethoxycarbonylpiperazin-1-yl)benzoyl]propionate

This ester was prepared in 43% yield by reaction of methyl3-(p-fluorobenzoyl) propionate with 1-ethoxy-carbonyl piperazine indimethylsulphoxide in the presence of potassium carbonate at 100°C for30 hours. It had m.p. 119°-120°C (from methanol).

b. 3-(4-Piperazin-1-yl)benzoylpropionic acid hydrochloride

This acid was prepared by hydrolysis of the foregoing ester with 2 moleequivalents of sodium hydroxide in 50 % aqueous ethanol followed byconcentration and acidification with hydrochloric acid. It was obtainedin 67% yield and had m.p. 255°-256°C (from methanol).

c. 6-(p-Piperazin-1-yl)phenyl-4,5 -dihydro-3(2H)-pyridazinonehydrochloride

The title compound was obtained in theoretical yield by reaction of theforegoing acid hydrochloride with 2 mole equivalents of hydrazinehydrate in ethanolic solution at reflux temperature for 5 hours. It hadm.p. 326°-327°C (with decomposition) (From 2-methoxyethanol).

EXAMPLE 14 6-(2,4 -Diethoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone a.3-(2,4 -Diethoxybenzoyl)propionic acid

A mixture of m-diethoxybenzene (22 g.) and succinic anhydride (15 g.)was dissolved in 1,2 -dichloroethane and the resultant solution wasstirred and treated with powdered aluminum chloride (30 g.), addedgradually during 1 hour with external cooling to keep the reactiontemperature at 10°C. The reaction mixture was stirred for 1 hourfurther, poured into water and the solvent was boiled off. The remainingoily suspension crystallized on stirring and cooling and the solid wascollected and dried (Yield 15.5 g.). It has m.p. 139°-141°C aftercrystallisation from toluene.

b. 6-(2,4 -Diethoxyphenyl)-4,5 -dihydro-3-(2H)-pyridazinone

A solution of the foregoing acid (8.0 g.) in hot ethanol (80 ml.) wastreated with hydrazine hydrate (1.8 ml.) and the solution was heated atreflux temperature for 4 hours. The product, which separated when thereaction mixture cooled, was collected and washed with methanol. It hadm.p. 148° - 150°C after crystallisation from ethanol (Yield 5.5 g.).

EXAMPLE 15 6-(o-Propoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone a.3-(o-Propoxybenzoyl)propionic acid

3-(o-Hydroxybenzoyl)propionic acid (14.6 g.) was dissolved in n-butanol(300 ml.) containing 85% potassium hydroxide (10 g.) and the resultantsolution was treated with 1-bromopropane (24.6 g.) and the mixtureheated at reflux temperature for 4 hours. It was then cooled, filteredto remove potassium bromide and the filtrate washed with cold water. Thebutanol was evaporated at reduced pressure and the residual oildistilled at 0.3 mm when the fraction b.p. 160°-180°C was collected(16.4 g.). This was dissolved in methanol (50 ml.), treated with 20 %sodium hydroxide solution (20 ml.) and heated on the steambath for 30minutes. The methanol was boiled off and the residue diluted with water(250 ml.) and acidified with hydrochloric acid. The precipitated acidwas collected and crystallised from 50% methanol. It had m.p. 77°-79°C(Yield 13.3 g.).

b. 6-(o-Propoxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone

This was obtained in 90% yield by reaction of the foregoing acid withhydrazine hydrate as described in earlier Examples. It had m.p.117.5°-119.5°C after crystallisation from aqueous methanol.

Similarly 6-(o-Pentyloxyphenyl)-4,5 -dihydro-3(2H)-pyridazinone (m.p.50°-52°C after crystallisation from aqueous methanol) was prepared from1-bromopentane in place of 1-bromopropane.

What is claimed is:
 1. A compound of the formula: ##SPC7##wherein X is:a straight or branched chain alkoxy group having 3-12 carbon atoms. 2.The compound of claim 1 wherein the alkoxy group is selected from thegroup consisting of propoxy, isopropoxy, methylbutoxy, butoxy,ethylpropoxy, hexyloxy, octyloxy, nonyloxy, decyloxy, ethylbutoxy,dodecyloxy, heptyloxy and pentyloxy.
 3. The compound of claim 1 which is6(p-hexyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone.